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基因交互作用大大影響胰臟癌病人對藥物的反應

    胰臟癌是非常惡性的腫瘤,病人的五年存活率在8-10%左右。因為胰臟癌不易早期發現,只有20%左右的病人可以開刀治療,在轉移的病人,目前化療大多是以Gemcitabine組合的藥物當作第一線的治療,然而藥物的反應率低,所以胰臟癌病人的存活率在近20年並無明顯的改善。

    精準醫學是癌症治療上非常重要的一環,不同的胰臟癌組織存在不同的基因缺陷,這些基因異常可單獨或協同活化不同的訊息傳遞途徑,所以癌症病人對化學或標靶治療的反應性有很大的差別。如何藉由細胞實驗,動物模式及病人基因檢測找到藥物反應的生物標記(Biomarker)是基礎研究人員與臨床醫師的共同目標。在胰臟癌中,變異最高的兩個基因是K-rasp53。然而除了這兩個基因外,常有第三個基因缺陷,本校洪文俊副校長領導的團隊發現WNT/β-catenin途徑的變異存在約20%的胰臟癌病人。團隊建立了基因轉殖鼠的動物模式,研究發現相較於只有K-rasp53變異的基因轉殖鼠,具有第三個WNT/β-catenin途徑基因缺陷的老鼠會特異性的增加血小板衍生生長因子(PDGF)基因轉錄,進而產生大量的PDGF來刺激胰臟癌細胞與星狀細胞生長,快速促進胰臟癌惡化轉移。進一步,團隊與國家衛生研究院及國立成功大學醫學院合作,在胰臟癌病人的血液與腫瘤組織印證了臨床相關性。更重要的,藉由分子機制探討及藥物篩選,團隊發現PDGF途徑特異性活化下游的訊息傳遞分子Src,所以具有三個基因缺陷的老鼠對Src抑制劑特別敏感,顯示此類藥物對具有特定基因變異的胰臟癌病人可能有更顯著的治療效果。此外血液PDGF的含量也可以是當作篩選病人的生物標記。本研究建立了新穎的胰臟癌動物模式來探討變異基因之交互作用對胰臟癌惡化與轉移的影響,同時找到了一個血液生物標記可用於篩選適合於標靶治療的胰臟癌病人(如圖示),達到精準醫療的目的,相關研究成果發表於國際期刊Theranostics

Genetic interplay greatly influences drug response of pancreatic cancer patients

本篇為高雄醫學大學2019年月傑出論文1月份得獎文章,代表作者為醫學院醫學研究所洪文俊教授。

論文出自https://www.thno.org/v09p0324.htm

Genetic interplay greatly influences drug response of pancreatic cancer patients

Pancreatic cancer is a deadly disease with five-year survival rate around 8-10%. Early detection of pancreatic cancer is difficult, therefore only 20% of patients can receive surgical resection at diagnosis. Gemcitabine-based chemotherapy is the first-line treatment for patients with metastasis, however the response rate is low. So, the survival of pancreatic cancer patients does not improve significantly in the past two decades.

    Precision medicine is important for cancer treatment. Pancreatic tumors have different genetic defects and the genetic abnormalities activate signal transduction pathways individually or synergistically, leading to distinct responses of cancer patients to chemotherapy or targeted therapy. How to identify biomarkers to predict drug response via cell-based experiments, animal models and patient genetic testing is a common goal of basic researchers and clinicians. In pancreatic cancer, the most highly mutated genes are K-ras and p53. However, in addition to these two genes, there is often a third genetic hit. The team led by Vice President Wen-Chun Hung of Kaohsiung Medical University found that about 20% of pancreatic cancer patients have genetic defects in the WNT/β-catenin pathway. They established various genetically modified mouse models and showed that mice with a third WNT/β-catenin pathway dysregulation will specifically increase the expression of platelet-derived growth factor (PDGF) compared to those with K-ras and p53 mutations. PDGF produced by cancer cells stimulates the proliferation of pancreatic cancer cells and stellate cells, and promotes the progression and metastasis of pancreatic cancer. In collaborating with National Health Research Institutes and National Cheng Kung University, they also verified the clinical relevance in the blood and tumor tissues of patients with pancreatic cancer. More importantly, through mechanistic study and drug screening, the team demonstrated that the PDGF pathway specifically activates the downstream signaling molecule Src, so mice with K-ras/p53/WNT dysregulations are particularly sensitive to Src inhibitors, suggesting that Src inhibitors may show greater therapeutic benefit on pancreatic cancer patients with specific genetic defects. Also, the blood PDGF content can be used as a biomarker for screening patients. This study establishes novel animal models to explore the genetic interplay on pancreatic tumorigenesis, and identifies a biomarker for selection of patients who may benefit from targeted therapy, the goal of precision medicine. The results have been published in the journal Theranostics.

Genetic interplay greatly influences drug response of pancreatic cancer patients

This article-“Beta-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer” , written by Rept. Author Professor Wen-Chun Hung, from Graduate Institute of Medicine, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in Jan.

Paper is available online at https://www.thno.org/v09p0324.htm

乾癬介紹

乾癬是一常見的免疫調節發炎性疾病,特徵是皮膚有帶皮屑的紅色斑塊,並且常合併其他疾病如關節炎和心血管疾病。乾癬的成因和多種基因與環境因子有關,本研究團隊和加州大學戴維斯分校合作,致力於研究飲食對乾癬的影響。

肥胖、飲食和乾癬

肥胖和乾癬的相關性已廣為人知,肥胖會惡化乾癬,肥胖的病人減重之後則會改善乾癬。然而,飲食中的脂肪和糖(例如蔗糖),都會引發肥胖,一般人常接觸到的是西方飲食(Western dietWD),這種飲食不只是攝取過多脂肪,也會從含糖飲料等來源攝取過多的糖。另一方面,探討肥胖和疾病關係的動物實驗,常常使用脂肪含量高但含糖量正常的配方(以下簡稱高脂飲食,high-fat dietHFD)來誘導肥胖,本研究主要是想比較西方飲食和高脂飲食,在同樣會誘導肥胖的前提下,對乾癬性發炎的影響是否有所不同。

西方飲食、高脂飲食和乾癬

實驗設計上,將小鼠分成四組,分別餵食WDcontrol diet(CD,即WD的對照組配方)HFDlow-fat diet(LFD,即HFD的對照組配方),在餵食小鼠三個月後,在耳朵塗抹imiquimod cream連續五天以誘導乾癬性皮膚炎,期間測量小鼠兩耳的厚度作為發炎水腫程度的指標。塗抹imiquimod cream滿五天後,取耳朵觀察組織變化,並作RT-qPCR和組織染色檢視乾癬相關的發炎因子變化。

餵食小鼠滿三個月後,HFD組的小鼠體重顯著高於其他三個組別,換句話說,食用HFD配方的小鼠肥胖程度較食用WD配方的小鼠嚴重,然而,經過imiquimod cream塗抹五天去誘導乾癬性發炎,WD組和HFD組相比,WD組小鼠在第四天後耳朵水腫程度較嚴重,組織學的檢視也發現,WD組小鼠發炎細胞如嗜中性球浸潤程度較嚴重,且Munro microabscess的密度也較高,用RT-qPCR檢視發炎因子的表現,也發現WD組的IL-17ALy6gIL-6等表現顯著較HFD組高。

結論西方飲食誘導乾癬,食物中的高糖組成可能是一大關鍵。

綜合所述,在這個實驗所用的配方,雖然HFDWD更會誘導肥胖,但是在小鼠imiquimod誘導乾癬性發炎的模式中,反而是WD組的乾癬性發炎較嚴重,依據此發現,對於乾癬病人的衛教可能不只要注意體重的控制,也要避免攝取過多糖類。將來需要更多的轉譯醫學研究和人類資料庫研究來驗證此實驗結果。

02 圖示 乾癬

圖說西方飲食(高脂高糖飲食),相較於高脂低糖飲食和常規飲食,會引發較多的IL-17細胞激素表現,此細胞激素對乾癬性發炎扮演重要角色。當遇到誘發因子,例如imiquimod藥膏,接受西方飲食的小鼠會有顯著的發炎性細胞激素表現增加,也會有較多的嗜中性球聚集,如果和接受高脂低糖飲食或常規飲食的小鼠比較,接受西方飲食的小鼠會有較嚴重的乾癬樣皮膚炎,顯示西方飲食中的高糖成分對乾癬性發炎扮演重要角色。

Introduction of psoriasis

Psoriasis is a common, immunologically mediated, inflammatory disease characterized by scaly erythematous plaques on the skin and have comorbidities such as arthritis and cardiovascular disease. Pathogenesis of psoriasis involves polygenic predisposition and multiple environmental factors. Our team has collaborated with University of California Davis to investigate the effects of diets on psoriasis.

Obesity, diets, and psoriasis

The relationship between obesity and psoriasis is well known. Obesity exacerbates psoriasis while body weight reduction ameliorates psoriasis. However, both fat and sugars (ex. sucrose) induces obesity, and general people more often eats the Western diet (WD, high-fat and high-sugar content), which not only contains excessive fat but has excessive sugars from sugary drinks. On the other hand, the high-fat diet (HFD, high-fat and normal sugar content) is also used in animal experiments to investigate the relationship between obesity and disease. In this research, we aim at investigating if there is difference in psoriasiform inflammation between WD and HFD, both induce obesity. 

WD, HFD, and psoriasis

For study design, mice were classified into four groups based on the diets: WD, control diet (CD, a control recipe of WD), HFD, low-fat diet (LFT, a control recipe of HFD). After feeding them for 3 months, we applied imiquimod cream on ears of mice for 5 consecutive days to induce psoriasiform dermatitis, and measure ear thickness as an indicator of inflammation during the course. After applying imiquimod cream for 5 days, mice were sacrificed and their ears were harvested to examine histological change, RT-qPCR and immunohistochemistry specific to psoriasis-related inflammatory mediators.

After feeding for 3 months, mice fed with HFD had significantly more body weight than other groups. This is, mice fed with HFD had more severe obese than mice fed with WD. After applying imiquimod cream for 5 consecutive days to induce psoriasiform dermatitis, however, mice fed with WD had more severe ear swelling after day 4. Histological analysis also demonstrated that mice fed with WD had more neutrophils and higher density of Munromicroabscess as well as higher expression levels of IL-17A, Ly6g, IL-6 than mice fed with HFD.

Conclusion: WD induces psoriasis, and the high-sugar content may play a crucial role.

Taken together, while HFD induced more obesity than WD in these recipes, it was WD group that had more severe psoriasiform inflammation in terms of the murine imiquimod model. According to this finding, health education for patients with psoriasis should not only focus on body weight control but avoid excessive sugar intake. Further translational medicine investigation and human database research are need to verify these experimental results. 

02 圖示 乾癬2

人格特質與糖尿病有關,強化飲食及運動自我照顧行為有解

高雄醫學大學護理學院王瑞霞教授,2019年指導碩士班研究生,進行200位第二型糖尿病人與人格特質的研究時,發現糖尿病人中,性格為外向的、友善的、謹慎性的病人,他們的糖尿病自我照顧行為比較好;也發現神經性人格異常的病人,糖尿病自我照顧行為比較差;另發現開放性人格與糖尿病自我照顧行為沒有明顯的相關。研究者同時發現,糖尿病自我照顧行為中,以飲食控制及運動行為與人格特質有比較強的關係,而飲食及運動自我照顧行為,正是國內糖尿病病人自我照顧行為執行最差的兩項。 

高醫大的研究結果提供臨床專業人員重要的線索,可以依照病人的人格特質不同,提供不同的衛生教育策略。糖尿病病人為避免合併症發生,須進行飲食控制、藥物、 血糖監測、高低血糖處理及足部照護等自我照顧行為,但也因這些行為會干擾病人日常生活而影響其持續性,專業人員也試圖找出影響行為的重要因素,以做為擬定策略的參考。因此,此糖尿病人與其人格特質的前瞻研究,為台灣的糖尿病照護增加新的照護知識,預期可以幫助更多糖尿病病人提升自我照護能力。 

高醫大護理學院王瑞霞教授從事第一型糖尿病青少年及第二型糖尿病已近12年,共發表30多篇糖尿病相關論文,並刊登於國際優良期刊。她的研究著重於探討心理社會因子對糖尿病的影響,也發展量表以做為臨床評估病人心理社會問題參考,她強調除了藥物治療外,不應忽略糖尿病個案在心理社會層面的照護,也因她在糖尿病的全方位研究及表現,王瑞霞教授獲得2017 年傑出護理人員專業貢獻獎,並多次獲得學校優秀論文獎及研究成果績優等獎項。 

王瑞霞強調,該研究提供專業人員在衛教病人自我照顧行為時,可先了解糖尿病人的人格特質,擬定適合人格特質的照護計畫,如針對具外向性人格特質者,可利用其積極主動個性,提供最新資訊鼓勵其持續執行自我照顧行為;謹慎性人格特質者則,可以較有組織的方式提供相關訊息;友善性人格特質者則可以較開放溝通的方式與病人討論自我照顧行為的執行;神經性人格特質者則應鼓勵其正向看待其罹病,避免因負向情緒反而放棄自我照顧行為的執行。 

護理學院 2017年王瑞霞教授獲傑出護理人員獎

2017年王瑞霞教授獲傑出護理人員獎

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